Regenerative medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects. This field holds the promise of regenerating damaged tissues and organs in the body by introducing outside cells, tissue, or even whole organs to integrate and become a part of tissues or replace whole organ. Importantly, regenerative medicine has the potential to solve the problem of the shortage of organs available for donation compared to the number of patients that require life-saving organ transplantation.
One key to the success of regenerative medicine strategies has been the ability to isolate and generate stem cells, including pluripotent stem cells. In one aspect, pluripotent stem cells can be differentiated into a necessary cell type, where the mature cells are used to replace tissue that is damaged by disease or injury. This type of treatment could be used to replace neurons damaged by spinal cord injury, stroke, Alzheimer's disease, Parkinson's disease, or other neurological problems. Cells grown to produce insulin could treat people with diabetes and heart muscle cells could repair damage after a heart attack. This list could conceivably include any tissue that is injured or diseased.
The generation of pluripotent stem cells that are genetically identical to an individual provides unique opportunities for basic research and for potential immunologically-compatible novel cell-based therapies. Methods to reprogram primate somatic cells to a pluripotent state include differentiated somatic cell nuclear transfer, differentiated somatic cell fusion with pluripotent stem cells, and direct reprogramming to produce induced pluripotent stem cells (iPS cells) (Takahashi K, et al. (2007) Cell 131:861-872; Park I H, et al. (2008) Nature 451:141-146; Yu J, et al. (2007) Science 318:1917-1920; Kim D, et al. (2009) Cell Stem Cell 4:472-476; Soldner F, et al. (2009) Cell. 136:964-977; Huangfu D, et al. (2008) Nature Biotechnology 26:1269-1275; Li W, et al. (2009) Cell Stem Cell 4:16-19).
A significant first hurdle in stem cell-based therapy is the differentiation of pluripotent cells into a desired tissue type. Such methods currently rely on the step-wise introduction of factors and conditions to guide the cells down a developmental pathway, resulting eventually in a mature or committed progenitor cell that can transplanted into a patient.
The promise of pluripotent stem cells is that they can form any type of cell in the body. The trouble is that when implanted into an animal they do just that, forming all tissue types in the form of teratomas. These teratomas are one reason why it is necessary to mature the embryonic stem cells into highly purified adult cell types before they are considered appropriate for implanting into humans. The mature cells are restricted to their one identity and don't appear to revert to a teratoma-forming cell. However, even when researchers have learned to mature cells into a single cell type, getting those cells pure enough to eliminate the risk of remaining immature cells forming teratomas has been extremely difficult.
Clinical applications may utilize billions of cells injected into large numbers of clinically diverse patients, many of whom will be expected to live out their whole lifetimes (i.e. pediatric patients). As such it is important to thoroughly deplete residual pluripotent stem cells.
A caveat to the clinical application of ES/iPS derived derivatives is that the in vivo implantation of even trace amounts of undifferentiated cells may result in uncontrolled teratomas. The present invention addresses this issue.